A3 Receptor Antagonists

Nonpurines - Leads for novel A3 antagonists have been obtained from compounds known to inhibit adenosine receptors and from library screening. The triazoloquinazoline derivative CGS15943 (19), previously known as a nonselective adenosine antagonist at the human subtypes, served as template for related nonpurine heterocyclic antagonists of the human A3 receptor, due to the observation of its high affinity (K, - 10 nM). Acylation of the //-amino group of 19 led to MRS 1220 (20) which is potent (Kj = 0.65 nM) and selective for human, but not rat A3 receptors (29). In a related series of heterocyclic derivatives, the pyrazolotriazolopyrimidine derivative MRE3008-F20 (21.) was found to be a highly selective antagonist at the human A3 receptor and was radiolabeled to provide a hydrophobic, but useful radiotracer with a K<j = 0.80 nM (30). Another analogue (22) in the same series displayed a K, = 0.16 nM at the A3 receptor (31). A pyridinium moiety (23) was introduced to enhance water-solubility in this series of A3 antagonists (32).


The earliest reported A3 antagonists were the result of library screening in which novel heterocyclic antagonists derivatives were identified (3,33,34): L-249313 (24, Ki = 13 nM) and L-268605 (25, K = 18 nM), flavonoids (MRS1067, 26, Ki = 560 nM), and dihydropyridines (27, 28). The dihydropyridines are typically antagonists of L-type Ca2+ channels; however, the addition of extended (arylalkene or arylalkyne) groups at the 4-position and phenyl substituents at the 6-position combined to eliminate recognition at the Ca2+ channels. Chiral resolution of MRS1191 (27) was carried out to identify the more active isomer, although the racemic 4-nitro derivative MRS1334 (28) was the most potent in this series (K, = 2.7 nM).


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